Many degenerative neurologic disorders appear to have a primary basis in mitochondrial dysfunction and more specifically in dysfunction of the electron transport chain. Because of the non- Mendelian genetics of some of the electron transport chain proteins which are inherited on the mitochondrial genome, the pattern of inheritance of some of these disorders such as kearns- Sayre syndrome (KSS), and some of the "mitochondrial myopathies" has been difficult to analyze. In fact, some of these disorders have been considered sporadic rather than genetic. Study of these disorders has been severely hampered by the extreme difficulty encountered in obtaining adequate amounts of mitochondria. We have recently developed a method for purifying previously unobtainable amounts of human mitochondria (25-40 mg mitochondrial protein) from patient platelets collected by plateletpheresis. Using this method we have been able to employ standard but previously unusable biochemical methods. We will study patient mitochondria using standard catalytic assays, inhibitor titrations, aborbance and electron paramagnetic resonance spectroscopy, and ultimately immunologic methods. These approaches will define catalytic deficiencies resulting from mutations in proteins containing redox prosthetic groups and those that do not but which are required for electron transport of assembly of redox complexes. This project will lead both to a better understanding of the disorders studied and to a more general understanding of mitochondrial genetics and their influence on the brain.